EXCEED THE SPACE PROVIDED. Convergent lines of evidence indicate that certain cognitive abnormalities in schizophrenia, such as deficits in working memory, are attributable to dysfunction of the dorsal prefrontal cortex (dPFC). This dysfunction appears to be associated with alterations of the neural circuitry within the dPFC, including disturbances in markers of inhibitory neurotransmission that are restricted to a subset of GABA neurons. During the current period of funding, we conducted studies designed to identify the affected subset of GABA neurons, to define the postsynaptic consequences of the alterations in these neurons, and to characterize the mechanisms that may produce these alterations. We found that 1) the chandelier cell population of GABA neurons exhibits expression deficits in multiple genes; 2) these changes are accompanied by an up-regulation of the <x2 subunit of the GABAA receptor at the postsynaptic target of chandelier neurons, the axon initial segment of pyramidal neurons; and 3) the alterations in chandelier neurons are likely to be downstream effects of impaired neurotrophin signaling through TrkB receptors and not to result from a reduced excitatory drive from the mediodorsal thalamus. The results of these studies have both illuminated the nature of GABA disturbances in the dPFC and identified a molecular target (as well as providing the neurobiological rationale) for a novel pharmacological intervention to enhance dPFC- mediated cognitive function in schizophrenia. Based on the results of these studies, during the next period of funding we plan to pursue seven new specific aims that cluster into two themes. First, we will further characterize the pathogenetic mechanisms and the pathophysiological consequences of the alteration in chandelier neuron inputs to pyramidal cells in schizophrenia (see sections d.1-4). Second, our microarray studies of GABA-related genes suggested that, in addition to chandelier neurons, other aspects of dPFC GABA neurotransmission might also be disturbed in schizophrenia. Thus, we plan to verify these observations and to determine how these gene expression changes may affect the functional circuitry of the dPFC (see sections d.5-7). As during the current period of funding, the overall goal of these studies is to determine the neurobiological basis of dPFC dysfunction in schizophrenia, to use these findings to identify and validate potential drug targets, and to translate these findings into novel pharmacological approaches for improving cognitive processing in individuals with schizophrenia.